Key Selectivity Controlling Elements in Rhodium-Catalyzed C–H Functionalization with Donor/Acceptor Carbenes

Computational studies on the dirhodium(tetracarboxylate)-catalyzed C–H functionalization with donor/acceptor carbenes reveal that the enantioselectivity and site-selectivity of this reaction are controlled by the ratio of conformers of both the diazo compound and the dirhodium carbene intermediates and two distinct steps of the reaction, namely, nitrogen extrusion and carbene insertion in the functionalized C–H bond. In these studies, we used trichloroethyl phenyldiazoacetate as the carbene precursor, p-isopropyltoluene as the substrate, and dirhodium-tetraacetate and a chiral dirhodium complex, Rh2(S-p-BrTPCP)4, as the catalysts. While the aryldiazoacetate exists in two conformers, we found that the reaction is not under Curtin Hammett conditions because the barrier for nitrogen extrusion is less than the barrier for interconversion of aryldiazoacetate conformers. The resulting dirhodium carbene intermediates exist as a diastereomeric mixture, the ratio of which is governed by the ratio of the aryldiazoacetate conformers and the influence of the chiral catalyst on the nitrogen extrusion. The diastereomeric rhodium carbene complexes can, in principle, interconvert through rotation, but the barrier for rotation is greater than the barrier for benzylic C–H functionalization. Thus, the two diastereomeric rhodium carbene complexes have different influences on the site- and enantioselectivity of the reaction. In the particular case with the Rh2(S-p-BrTPCP)4-catalyzed reaction, the major rhodium carbene diastereomer is calculated to be the matched case, reacting in a highly enantioselective manner, whereas the minor rhodium carbene diastereomer gives low enantioselectivity. The overall predicted enantioselectivity of the reaction, 98.9:1.1 er, is in close agreement with its observed value of 97.5:2.5 er.